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Contraindications
Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the
formulation.
Esomeprazole like other PPIs should not be administered with atazanavir (see "Interactions").
Special warnings and special precautions for use
In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy
should be excluded, as treatment with Nexium may alleviate symptoms and delay diagnosis.
Patients on long-term treatment (particularly those treated for more than a year) should be kept under
regular surveillance.
Patients on on-demand treatment should be instructed to contact their physician if their symptoms
change in character. When prescribing esomeprazole for on demand therapy, the implications for
interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole
should be considered (see "Interactions").
When prescribing esomeprazole for eradication of
Helicobacter pylori possible drug interactions for all
components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4
and hence contraindications and interactions for clarithromycin should be considered when the triple
therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 such as cisapride.
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance,
glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Interactions
Effects of esomeprazole on the pharmacokinetics of other drugs
Medicinal products with pH dependent absorption
The decreased intragastric acidity during treatment with esomeprazole, might increase or decrease the
absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the
use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can
decrease during treatment with esomeprazole.
Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy
volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in
AUC, Cmax and Cmin). Increasing the atazanavir dose to 400 mg did not compensate for the impact of
omeprazole on atazanavir exposure. PPIs including esomeprazole should not be co-administered with
atazanavir (see "Contraindications").
Drugs metabolised by CYP2C19
Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when
esomeprazole is combined with drugs metabolised by CYP2C19, such as diazepam, citalopram,
imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased
and a dose reduction could be needed. This should be considered especially when prescribing
esomeprazole for on demand therapy. Concomitant administration of 30 mg esomeprazole resulted in a
45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of 40 mg
esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is
recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole
is introduced or withdrawn. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19
substrate) Cmax and AUCT by 15% and 41%, respectively.
Concomitant administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed
that coagulation times were within the accepted range. However, post-marketing, a few isolated cases
of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is
recommended when initiating and ending concomitant esomeprazole treatment during treatment with
warfarin or other coumarine derivatives.
In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase
in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t½) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc
interval observed after administration of cisapride alone, was not further prolonged when cisapride was
given in combination with esomeprazole. (See "Special warnings and special precautions for use").
Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of
amoxicillin or quinidine.
Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not
identify any clinically relevant pharmacokinetic interactions during short-term studies.
Effects of other drugs on the pharmacokinetics of esomeprazole
Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole
and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to
esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and
CYP 3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4
inhibitor voriconazole increased omeprazole AUCT by 280%. A dose adjustment of esomeprazole is
not regularly required in either of these situations. However, dose adjustment should be considered in
patients with severe hepatic impairment and if long-term treatment is indicated.
Pregnancy and lactation
For Nexium, clinical data on exposed pregnancies are insufficient. With the racemic mixture
omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no
malformative nor foetotoxic effects. Animal studies with esomeprazole do not indicate direct or indirect
harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture
do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal
development. Caution should be exercised when prescribing to pregnant women.
It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women
have been performed. Therefore Nexium should not be used during breast-feeding.
Effects on ability to drive and use machines
No effects have been observed.
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